arsenic trioxide

Arsenic trioxide is a chemotherapy (antineoplastic) drug used to treat acute promyelocytic leukemia (APL), an aggressive type of blood cancer. APL is a subtype (M3) of acute myeloid leukemia (AML), a group of blood cancers that causes excessive proliferation of immature blood cells (promyelocytes) in the bone marrow. The different subtypes of AML are caused by different genetic mutations and treatment can differ based on the subtype.

Acute promyelocytic leukemia is caused by a genetic mutation resulting from a chromosomal translocation that fuses promyelocytic leukemia (PML) gene and retinoid acid receptor-alpha (RAR-A) gene, which results in production of PML-RAR alpha fusion protein. The abnormal fusion protein blocks the maturation and differentiation of white blood cells that lead to the proliferation of immature cells, and shortage of normal white and red blood cells, and platelets.

Arsenic is a naturally occurring toxic metallic element. The mechanism of action of arsenic trioxide in the treatment of APL is not completely understood. Arsenic trioxide causes structural changes and fragmentation of the cancer cell DNA and induces programmed cell death (apoptosis) in human promyelocytic leukemia cells, in lab tests. Arsenic trioxide also damages and degrades the PML-RAR alpha fusion protein.

Arsenic trioxide is administered through intravenous infusion and is approved by the FDA for:

• Treatment of newly diagnosed low-risk acute promyelocytic leukemia, in combination with tretinoin, in adults whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression
• Remission induction and consolidation treatment of acute promyelocytic leukemia in patients 4 years or older who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression

Off-label uses of arsenic trioxide in adults include:

• Newly diagnosed intermediate-risk or high-risk acute promyelocytic leukemia

Orphan designations (adults):

• Myelocytic leukemia subtypes MO, M1, M2, M4, M5, M6, and M7
• Chronic lymphocytic leukemia
• Malignant glioma
• Myelodysplastic syndrome
• Multiple myeloma
• Liver cancer
• Chronic myeloid leukemia
• Amyotrophic lateral sclerosis
• Acute promyelocytic leukemia (oral capsule)
• Graft-versus-host disease

• Do not administer arsenic trioxide to patients with hypersensitivity to arsenic or any component of the formulation.
• Arsenic trioxide therapy can cause differentiation syndrome, a life-threatening or fatal reaction that can occur as early as the first day of induction or as late as second month of induction therapy, with or without high white blood cell count (hyperleukocytosis).
  • Symptoms include unexplained fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusion, weight gain, peripheral edema, hypotension, renal insufficiency, hepatopathy and multi-organ dysfunction.
  • Use prednisone as prophylaxis when arsenic trioxide is used in combination with tretinoin.
  • Interrupt arsenic trioxide at the first sign of differentiation syndrome and administer dexamethasone until signs and symptoms have abated for at least 3 days.
• Arsenic trioxide can cause heart conduction abnormalities in patients, including QTc prolongation, torsades de pointes, a type of ventricular arrhythmia that can be fatal, and complete heart block. Before initiating arsenic trioxide:
  • Assess the patient’s QTc interval, correct pre-existing electrolyte abnormalities and discontinue other drugs that can cause QTc prolongation.
  • Do not administer arsenic trioxide to patients with prolonged QTc or ventricular arrhythmia.
  • If a patient develops prolongation of QTc during treatment, withhold arsenic trioxide, correct electrolyte abnormalities, and resume treatment with reduced dose after QTc becomes normal.
• Arsenic trioxide can cause brain damage (encephalopathy) including Wernicke’s encephalopathy, which can be prevented and treated with thiamine.
  • Symptoms of encephalopathy include decreased level of consciousness, confusion, seizures, cognitive deficits, ataxia, visual symptoms and ocular motor dysfunction.
  • Monitor patients for neurological symptoms and nutritional status. Interrupt arsenic trioxide if Wernicke’s encephalopathy is suspected and administer intravenous thiamine.
  • Inform patients and caregivers of neurological symptoms to be alert for and advise them to report immediately if they experience any.
• Arsenic trioxide can cause fetal harm, advise women of pregnant potential and men with women partners with pregnancy potential to practice effective contraception during and for the recommended period after the completion of treatment. If a patient becomes pregnant during treatment, apprise the patient of potential hazard to the fetus.
• Arsenic trioxide can damage the liver. Monitor patient’s liver function and if liver toxicity occurs, withhold treatment until it is resolved.
• Use arsenic trioxide with caution in patients with impaired liver or kidney function.
• Arsenic trioxide is a known human carcinogen. Monitor patients for second primary malignancies.

Common side effects of arsenic trioxide include:

• Nausea
• Vomiting
• Abdominal pain
• Diarrhea
• Constipation
• Reduced appetite
• Loss of appetite (anorexia)
• Indigestion (dyspepsia)
• Loose stools
• Fecal incontinence
• Abdominal distension
• Abdominal tenderness
• Gastrointestinal hemorrhage
• Hemorrhagic diarrhea
• Dry mouth
• Oral blistering
• Sore throat
• Cough
• Shortness of breath (dyspnea)
• Nose bleed (epistaxis)
• Low tissue oxygen saturation (hypoxia)
• Fluid around lungs (pleural effusion)
• Post-nasal drip
• Wheezing
• Abnormal breathing sounds (crepitations, rales and ronchi)
• Decreased breath sounds
• Rapid breathing (tachypnea)
• Coughing up blood (hemoptysis)
• Headache
• Insomnia
• Abnormal skin sensations (paresthesia)
• Dizziness
• Tremor
• Convulsion
• Drowsiness (somnolence)
• Coma
• Rapid heart rate (tachycardia)
• Abnormal ECG readings
• Heart rhythm disturbance (prolonged QTc interval)
• Palpitations
• Fatigue
• Fever (pyrexia)
• Rigors
• Non-specific swelling (edema)
• Chest pain
• Non-specific pain
• Injection site reactions including:
  • Pain
  • Edema
  • Redness (erythema)
• Weakness
• Weight gain or loss
• Hemorrhage
• Drug hypersensitivity
• Electrolyte disturbances including:
  • Low or high potassium (hypokalemia or hyperkalemia)
  • Low magnesium (hypomagnesemia)
  • Low calcium (hypocalcemia)
• High or low blood glucose levels (hyperglycemia or hypoglycemia)
• Increase in levels of liver enzymes ALT and AST
• Excessive acidity of body fluids (acidosis)
• Blood disorders including:
  • High count of white cells (leukocytosis)
  • Low count of red blood cells (anemia)
  • Low platelet count (thrombocytopenia)
  • Low count of neutrophil immune cells (neutropenia)
  • Neutropenia with fever (febrile neutropenia)
• Blood clotting disorder (disseminated intravascular coagulation)
• Lymph node swelling (lymphadenopathy)
• Skin reactions including:
  • Dermatitis
  • Itching (pruritus)
  • Bruising (ecchymosis)
  • Dry skin
  • Non-specific erythema
  • Hives (urticaria)
  • Darkening of skin (hyperpigmentation)
  • Red or purple spots from bleeding beneath the skin (petechiae)
  • Skin lesions
  • Skin peeling (exfoliation)
• Increased sweating
• Night sweats
• Facial edema
• Eyelid edema
• Low or high blood pressure (hypotension or hypertension)
• Flushing
• Pallor
• Joint pain (arthralgia)
• Muscle pain (myalgia)
• Bone pain
• Back pain
• Neck pain
• Limb pain
• Anxiety
• Depression
• Confusion
• Agitation
• Sinus inflammation (sinusitis)
• Upper respiratory tract infection
• Herpes simplex
• Herpes zoster
• Bacterial infection
• Oral Candida yeast infection (candidiasis)
• Nose and throat inflammation (nasopharyngitis)
• Sepsis
• Eye irritation
• Blurred vision
• Dry eye
• Painful red eye
• Earache
• Ringing in the ears (tinnitus)
• Vaginal hemorrhage
• Intermenstrual bleeding
• Kidney function impairment
• Kidney failure
• Urinary incontinence
• Reduced urine output (oliguria)

Less common side effects of arsenic trioxide include:

• Heart conduction disorders including:
  • QT prolongation with:
    • Extra ventricular beats (extrasystoles)
    • Ventricular tachycardia (torsades de pointes)
  • Atrioventricular block
• Congestive heart failure
• Peripheral nerve damage (neuropathy)
• Confusion
• Muscle weakness (paresis)
• Seizures
• Encephalopathies including:
  • Wernicke’s encephalopathy
  • Posterior reversible encephalopathy syndrome
• Muscle tissue breakdown (rhabdomyolysis)
• Low count of all types of blood cells (pancytopenia)
• Bone marrow tissue death (necrosis)
• Increase in gamma-glutamyl transferase
• Differentiation syndrome
• Retinoid acid syndrome
• New tumors and cancers including:
  • Melanoma
  • Pancreatic cancer
  • Squamous cell carcinoma
• Deafness
• Severe skin reaction (toxic epidermal necrolysis)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Injectable solution

• 1 mg/mL (10 mg ampule)

Adult:

Acute Promyelocytic Leukemia

Newly diagnosed low-risk acute promyelocytic leukemia (APL)

• Indicated in combination with tretinoin for treatment of adults with newly diagnosed low risk APL whose APL has the presence of the t(15;17) translocation or PML/RAR-alpha gene expression
• Treatment course consists of 1 induction and 4 consolidation cycles
• Induction cycle
  • Arsenic trioxide 0.15 mg/kg intravenous (IV) once daily until bone marrow remission; not to exceed 60 days, PLUS  
  • Tretinoin 22.5 mg/m² orally twice daily until bone marrow remission; not to exceed 60 days
  • Differentiation syndrome prophylaxis consisting of prednisone 0.5 mg/kg daily from day 1 until the end of induction therapy is recommended
• Consolidation cycle
  • Arsenic trioxide 0.15 mg/kg IV daily x Days 1-5 on Weeks 1-4 of an 8-week cycle for a total of 4 cycles in combination with tretinoin
  • Tretinoin 22.5 mg/m² orally twice daily x Days 1-7 on Weeks 1, 2, 5, 6; omit tretinoin during weeks 5-6 of the fourth cycle of consolidation

Relapsed or refractory APL

• Indicated for induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression
• Treatment course consists of 1 induction and 1 consolidation cycle
• Induction cycle
  • Arsenic trioxide 0.15 mg/kg IV once daily until bone marrow remission; not to exceed 60 days  
• Consolidation cycle
  • Begin consolidation 3-6 weeks after completion of induction therapy
  • Arsenic trioxide 0.15 mg/kg IV daily for 25 doses over a period of up to 5 weeks

Dosage Modifications

Differentiation syndrome

• Defined by the presence of 2 or more of the following: Unexplained fever, dyspnea; pleural and/or pericardial effusion; pulmonary infiltrates; renal failure; hypotension; weight gain of more than 5 kg
• Temporarily withhold arsenic trioxide
• Consider holding tretinoin if symptoms are severe
• Treat with dexamethasone 10 mg IV every 12 hours until resolution of signs and symptoms for a minimum of 3 days
• Resume treatment when the clinical condition improves and reduce dose of the withheld drug(s) by 50%
• After 7 days on the reduced dose in the absence of differentiation syndrome, increase dose of withheld drug(s) to recommended dosage
• If symptoms reappear, decrease arsenic trioxide and/or tretinoin to previous dose

QTc Prolongation

• QTc prolongation above 450 msec (men) or above 460 msec (women)
• Withhold treatment and any medication known to cause QT prolongation
• Replete electrolytes
• After QTc normalizes, resume arsenic trioxide at a 50% reduced dose (0.075 mg/kg once daily) for 7 days
• If the 50% reduced dose is tolerated for 7 days (in the absence of QTc prolongation), increase dose to 0.11 mg/kg once daily for 7 days
• Dose can be increased to 0.15 mg/kg in the absence of QTc prolongation during that 14-day dose escalation period

Hepatoxicity

• Defined by 1 or more of the following: Total bilirubin (TB) above 3 times upper limit of normal (ULN); AST above 5 times ULN; alkaline phosphatase (AP) above 5 times ULN
• Withhold treatment with arsenic trioxide and/or tretinoin
• Resume treatment at a 50% reduced dose of the withheld drug(s) when TB is below 1.5 times ULN and AP/AST are below 3 times ULN
• After 7 days on the reduced dose in the absence or worsening of hepatotoxicity; increase dose of withheld drug(s) back to recommended dosage
• Permanently discontinue the withheld drug(s) if hepatotoxicity recurs

Other severe or life-threatening (grade 3-4) nonhematologic reactions

• Temporarily withhold arsenic trioxide and tretinoin
• When adverse reaction resolves to grade 1 or lower, resume treatment reduced by 2 dose levels (see below)

Moderate (grade 2) nonhematologic reactions

• Reduce the dose of arsenic trioxide and/or tretinoin by 1 dose level (see below)

Leukocytosis (WBC count above 10 Gi/L)

• Administer hydroxyurea
• Discontinue hydroxyurea when WBC below 10 Gi/L

Myelosuppression

• Defined by 1 or more of the following: ANC below 1 Gi/L; platelets below 50 Gi/L lasting more than 5 weeks
• Consider reducing dose of arsenic trioxide and tretinoin by following: 1 dose level (see below)
• If myelosuppression lasts 50 days or longer or occurs on 2 consecutive cycles, assess a marrow aspirate for remission weeks status
• In the case of molecular remission, resume treatment at 1 dose level lower

Dosing reduction levels for hematologic and nonhematologic toxicities

Arsenic trioxide

• Starting level: 0.15 mg/kg IV once daily
• Level -1: 0.11 mg/kg IV once daily
• Level -2: 0.1 mg/kg IV once daily
• Level -3: 0.075 mg/kg IV once daily

Tretinoin

• Starting level: 22.5 mg/m² orally twice daily
• Level -1: 18.75 mg/m² orally twice daily
• Level -2: 12.5 mg/m² orally twice daily
• Level -3: 10 mg/m² orally twice daily

Renal impairment

• Severe: (creatinine clearance [CrCl] below 30 mL/min): Exposure of arsenic trioxide may be higher; monitor for toxicities and dose reduce when warranted
• Dialysis: Safety and efficacy not established

Hepatic impairment

• Limited data available for all hepatic impairment groups; use with caution
• Severe (Child Pugh C): Monitor for toxicities

Pediatric:

Acute Promyelocytic Leukemia

Refractory or relapse after retinoid and anthracycline chemotherapy

• Indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression
• Children below 4 years: Safety and efficacy not established
• Children 4 years and above: 0.15 mg/kg IV once daily until bone marrow remission; not to exceed 60 doses  
• Wait 3-6 weeks, THEN
• 0.15 mg/kg IV once daily for 25 doses (administered over time period of up to 5 weeks)

Dosing Considerations

• Monitor: ECG, serum electrolytes

Overdose

• Arsenic is a naturally toxic element and overdose can cause convulsions, muscle weakness and confusion. If a patient develops overdose symptoms, arsenic trioxide should be immediately discontinued and chelation therapy may be considered to eliminate the drug.
• Conventional treatment for arsenic trioxide overdose includes administration of dimercaprol 3 mg/kg intramuscularly every 4 hours until immediate life-threatening toxicity has subsided, and thereafter, 250 mg oral penicillamine up to 4 times a day.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of arsenic trioxide include:
  • artemether/lumefantrine
  • dronedarone
  • epinephrine racemic
  • erythromycin base
  • erythromycin ethylsuccinate
  • erythromycin lactobionate
  • erythromycin stearate
  • goserelin
  • leuprolide
  • nilotinib
  • octreotide (Antidote)
  • pimozide
  • trazodone
  • ziprasidone
• Arsenic trioxide has serious interactions with 122 different drugs.
• Arsenic trioxide has moderate interactions with 50 different drugs.
• Arsenic trioxide has no listed mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no adequate and well-controlled studies on the use of arsenic trioxide in pregnant women, however, animal studies show it can cause fetal harm. One patient who became pregnant during treatment with arsenic trioxide had a miscarriage.
• Women of reproductive potential should use effective contraception during treatment with arsenic trioxide and for 6 months after the final dose. Men with women partners of reproductive potential should use effective contraception during treatment with arsenic trioxide and for 3 months after the final dose.
• Arsenic trioxide is present in breastmilk. Discontinue breastfeeding while on treatment with arsenic trioxide because of the potential for serious adverse reactions in the breastfed infant.

• Inform your physician immediately if you experience:
  • Differentiation syndrome symptoms, which may include fever, sudden weight gain, dizziness/lightheadedness, labored breathing, and accumulation of fluid in the lungs, heart, and chest.
  • Heart conduction abnormalities such as irregular heartbeats or fainting.
  • Symptoms of encephalopathy including reduced level of consciousness, confusion, cognitive deficits, seizures, impaired balance, coordination and balance, visual symptoms and eye movement dysfunction.
• Notify your physician immediately if you suspect administration of an overdose.